The classification of antimicrobial agents based on their mechanism of action, that is, based on the biochemical reactions they affect, forms the foundation in understanding the antimicrobial agents. This fundamental knowledge has proven to be very useful while dealing and prescribing antimicrobial agents in our daily clinical practice.
Drugs Affecting Metabolic Pathways
Bacterial Folate Synthesis
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Sulfonamides : Contain the sulfanilamide moiety - a structural analogue of PABA, which is essential in bacterial folate synthesis. It competes with PABA, and inhibits bacterial growth, without affecting mammalian cell function.
- Sulfadiazine
- Sulfamethoxazole
- Sulfadoxine
- Sulfamethopyrazine
- Sulfacetamide sodium
- Sulfasalazine
- Silver sulfadiazine
- Mafenide
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Diaminopyrimidine : Inhibits bacterial dihydrofolate reductase, which reduces dihydrofolate to tetrahydrofolate.
- Trimethoprin
- Pyrimethamine
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Proguanil
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*Co-trimoxazole - contains both a sulfonamide and trimethoprim
Drugs Affecting Anabolic Pathways
- They act on pathways that convert small molecules into macromolecules such as protein, nucleic acids and peptidoglycans.
Synthesis of Peptidoglycan
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Beta lactams : Inhibits the final transpeptidation by forming covalent bonds with penicillin-binding proteins so that cross linking (that maintains the close kit structure of the cell wall), does not take place.
- Penicillin
- Cephalosporins
- Monobactams
- Carbapenems
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Beta Lactamase Inhibitors : Binds with the beta lactamase enzyme produced by bacteria and inhibits it's action.
- Clavulanic acid
- Sulbactam
- Tazobactam
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Cycloserine : Structural analogue of D-Alanine, prevents the addition of the two terminal alanine residues to the initial tripeptide side chain on N-Acetylmuramic acid by competitive inhibition.
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Vancomycin : Inhibits the release of the building block unit from the carrier, thus preventing its addition to the growing end of the peptidoglycan.
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Bacitracin : Interferes with the regeneration of the lipid carrier by blocking its dephosphorylation.
Protein Synthesis
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The bacterial ribosome consists of a 50S subunit and a 30S subunit, whereas the mammalian ribosome have 60S and 40S subunits.
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Eukaryotes and prokaryotes have different ribosomes, which provides the basis for the selective antimicrobial action of some antibiotics.
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The other elements involved in protein synthesis are messenger RNA (mRNA), which forms the template for protein synthesis, and transfer RNA (tRNA) which specifically transfers the individual amino acids to the ribosome. The ribosomes have three binding sites for tRNA, named as A, P and E sites.
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Tetracyclines : Competes with tRNA for the A site - Binds to 30S ribosomes and blocks attachment of tRNA to mRNA-ribosome complex and hence, the peptide chain fails to grow.
- Oxytetracycline
- Doxycycline
- Minocycline
- Demeclocycline
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Aminoglycosides : Abnormal codon : anticodon leads to misreading of the message.
- Streptomycin
- Gentamicin
- Kanamycin
- Tobramycin
- Amikacin
- Neomycin
- Framycetin
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Chloramphenicol : Specifically attaches to the 50S ribosome near the A site and prevents peptide bond formation between the newly attached amino acid and the nascent peptide chain.
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Puromycin : Premature termination of the peptide chain.
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Erythromycin, Spectinomycin, Fusidic acid : Inhibition of translocation.
Nucleic Acid Synthesis
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Acridines (Proflavine and Acrifavine) : Inhibition of nucleotide synthesis.
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Rifampicin and Rifamycin : Specific iniihibitors of RNA polymerase.
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Acyclovir : Is phosphorylated in cells infected with herpes virus, the initial phosphorylation being by a virus-specific kinase to give acyclovir triphosphate, which has an inhibitory action on the DNA polymerase of the herpes virus.
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Zidovudine, Didanosine : Are phosphorylated by cellular enzymes to triphosphate forms, which compete with the host cell precursors, essential for the formation of proviral DNA.
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Quinolones : Inhibits DNA gyrase (primarily active in gram negative bacteria), that nicks double stranded DNA, introduces negative supercoils and reseals the nicked ends (necessary for preventing excessive positive supercoiling of the strands). In gram positive bacteria, the major target is a similar enzyme Topoisomerase IV which nicks and separates daughter DNA strands after DNA replication.
- Nalidixic acid
- Fluoroquinolones - Ciprofloxacin, Norfloxacin, Ofloxacin, Pefloxacin, Levofloxacin, Moxifloxacin.
Drugs Acting on Plasma Membrane
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Polymixins : Act as detergents, disrupting the phospholipid components of the membrane structure, thus killing the cell.
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Polyenes : Act as ionophores and cause leakage of cations from the cytoplasm by attaching to fungal cell membranes that contain large amount of ergosterol.
- Nystatin
- Amphotericin
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Azoles (Itraconazole): Kills fungal cell by inhibiting ergosterol synthesis, thereby disrupting the function of membrane-associated enzymes. Also, affects gram-positive bacteria, as they have high levels of free fatty acids in the membrane.
Drugs Acting on Intracellular organelles
- Benzimidazoles (Albendazole) : Binds selectively to parasite tubulin and prevents micro-tubule formation.
- Chloroquine : Inhibits plasmodial haem polymerase.
- Avermectins : Increases chloride permeability in helminth muscle.
- Pyrantel : Agonists at nematode acetylcholine nicotinic receptors on muscle, causing contraction followed by paralysis.
References
- Essentials of Medical Pharmacology 8th Edition (K.D. Tripathi)-Jaypee Brothers Medical Publishers (P) Ltd.
- James Ritter, Rod Flower, Graeme Henderson, Yoon Kong Loke, David MacEwan, Humphrey Rang - Rang & Dale’s Pharmacology-Elsevier (2019).
- Laurence L. Brunton - Goodman & Gilman's Manual of Pharmacology and Therapeutics-McGraw-Hill Medical (2008).
*This article is an excerpt from the above mentioned books and Medical Sutras does not make any ownership or affiliation claims.